Cargando…

Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative

In 2005, the International Council for Harmonization (ICH) established cardiotoxicity assessment guidelines to identify the risk of Torsade de Pointes (TdP). It is focused on the blockade of the human ether-à-go-go-related gene (hERG) channel known to cause QT/QTc prolongation and the QT/QTc prolong...

Descripción completa

Detalles Bibliográficos
Autores principales: Park, Jin-Sol, Jeon, Ji-Young, Yang, Ji-Ho, Kim, Min-Gul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society for Clinical Pharmacology and Therapeutics 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989268/
https://www.ncbi.nlm.nih.gov/pubmed/32055576
http://dx.doi.org/10.12793/tcp.2019.27.1.12
_version_ 1783492371592249344
author Park, Jin-Sol
Jeon, Ji-Young
Yang, Ji-Ho
Kim, Min-Gul
author_facet Park, Jin-Sol
Jeon, Ji-Young
Yang, Ji-Ho
Kim, Min-Gul
author_sort Park, Jin-Sol
collection PubMed
description In 2005, the International Council for Harmonization (ICH) established cardiotoxicity assessment guidelines to identify the risk of Torsade de Pointes (TdP). It is focused on the blockade of the human ether-à-go-go-related gene (hERG) channel known to cause QT/QTc prolongation and the QT/QTc prolongation shown on the electrocardiogram. However, these biomarkers are not the direct risks of TdP with low specificity as the action potential is influenced by multiple channels along with the hERG channel. Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative emerged to address limitations of the current model. The objective of CiPA is to develop a standardized in silico model of a human ventricular cell to quantitively evaluate the cardiac response for the cardiac toxicity risk and to come up with a metric for the TdP risk assessment. In silico working group under CiPA developed a standardized and reliable in silico model and a metric that can quantitatively evaluate cellular cardiac electrophysiologic activity. The implementation mainly consists of hERG fitting, Hill fitting, and action potential simulation. In this review, we explained how the in silico model of CiPA works, and briefly summarized current overall CiPA studies. We hope this review helps clinical pharmacologists to understand the underlying estimation process of CiPA in silico modeling.
format Online
Article
Text
id pubmed-6989268
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Korean Society for Clinical Pharmacology and Therapeutics
record_format MEDLINE/PubMed
spelling pubmed-69892682020-02-13 Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative Park, Jin-Sol Jeon, Ji-Young Yang, Ji-Ho Kim, Min-Gul Transl Clin Pharmacol Review In 2005, the International Council for Harmonization (ICH) established cardiotoxicity assessment guidelines to identify the risk of Torsade de Pointes (TdP). It is focused on the blockade of the human ether-à-go-go-related gene (hERG) channel known to cause QT/QTc prolongation and the QT/QTc prolongation shown on the electrocardiogram. However, these biomarkers are not the direct risks of TdP with low specificity as the action potential is influenced by multiple channels along with the hERG channel. Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative emerged to address limitations of the current model. The objective of CiPA is to develop a standardized in silico model of a human ventricular cell to quantitively evaluate the cardiac response for the cardiac toxicity risk and to come up with a metric for the TdP risk assessment. In silico working group under CiPA developed a standardized and reliable in silico model and a metric that can quantitatively evaluate cellular cardiac electrophysiologic activity. The implementation mainly consists of hERG fitting, Hill fitting, and action potential simulation. In this review, we explained how the in silico model of CiPA works, and briefly summarized current overall CiPA studies. We hope this review helps clinical pharmacologists to understand the underlying estimation process of CiPA in silico modeling. Korean Society for Clinical Pharmacology and Therapeutics 2019-03 2019-03-27 /pmc/articles/PMC6989268/ /pubmed/32055576 http://dx.doi.org/10.12793/tcp.2019.27.1.12 Text en Copyright © 2019 Min-Gul Kim http://creativecommons.org/licenses/by-nc/3.0/ It is identical to the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/).
spellingShingle Review
Park, Jin-Sol
Jeon, Ji-Young
Yang, Ji-Ho
Kim, Min-Gul
Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative
title Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative
title_full Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative
title_fullStr Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative
title_full_unstemmed Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative
title_short Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative
title_sort introduction to in silico model for proarrhythmic risk assessment under the cipa initiative
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989268/
https://www.ncbi.nlm.nih.gov/pubmed/32055576
http://dx.doi.org/10.12793/tcp.2019.27.1.12
work_keys_str_mv AT parkjinsol introductiontoinsilicomodelforproarrhythmicriskassessmentunderthecipainitiative
AT jeonjiyoung introductiontoinsilicomodelforproarrhythmicriskassessmentunderthecipainitiative
AT yangjiho introductiontoinsilicomodelforproarrhythmicriskassessmentunderthecipainitiative
AT kimmingul introductiontoinsilicomodelforproarrhythmicriskassessmentunderthecipainitiative